In general therapeutic applications of ultrasound in the clinic may be divided into two major categories; applications that employ low intensity (0.125-3 W/cm2) and those that employ higher intensities (≧5 W/cm2) (ter Haar, (1999) Eur. J. Ultrasound 9:3). The former is commonly used in applications such as physiotherapy including the stimulation of normal physiological responses to injury or to accelerate some processes such as transport of drugs across the skin. Treatment with low intensity ultrasound rarely results in collateral tissue damage and indeed extreme efforts are employed to minimise such effects. This includes minimising excessive tissue heating as a result of exposure to the relevant dose of ultrasound. Usually this is accomplished by reducing the treatment time and/or delivering the ultrasound in a pulsed manner.
The major objective of applications involving the use of high intensity ultrasound is to selectively destroy tissue by hyperthermic processes. High intensity ultrasound-mediated tissue ablation may be further categorised on the basis in which the energy is delivered to the tissues. The ultrasound may be delivered directly from the transducer to the treatment area. Alternatively delivery may be mediated by a coupling device which results in focussing of the ultrasound. During the latter the ultrasound passing through intervening tissues is usually at low intensity and therefore relatively non-destructive. However at the focal point the accumulated energy is raised to a pre-determined higher intensity and tissue destruction occurs at or around that focal point. This has the advantage of being relatively selective and prevents major damage to intervening tissues.
In general the use of high intensity focussed ultrasound or HIFU exploits heating at the focal point and a number of methods together with devices for achieving focus and tissue ablation have been suggested (see U.S. Pat. Nos. 4,888,746, 5,895,356, 5,938,608 and International Patent Applications WO 9735518A1 and WO 9922652A1).
In addition to a requirement for relatively sophisticated equipment to achieve focussing of high intensity ultrasound, one major disadvantage associated with the use of HIFU involves the potential for the occurrence of cavitation events which, in turn, leads to the formation of destructive or possibly mutagenic free radicals (Miller et al., (1996) Ultrasound in Med. & Biol.22; 1131). An alternative approach involving a mechanism of sensitising the target tissue to low intensity ultrasound (either focussed or non-focussed) would therefore provide advantage.
It has been found that delivery of short, intense electric pulses to cell populations or tissues (in vivo) results in transient permeabilisation and this has provided the basis for what has become known as electrochemotherapy (Heller et al. Advanced Drug Delivery Rev.35,119;1999). It was originally developed to facilitate passage of chemotherapeutic drugs into cancer cells which had become impermeable to those drugs. It has since been developed to a stage where delivery of electric pulses in vivo is being exploited in areas such as gene therapy in order to mediate introduction of DNA to target areas. Devices designed to facilitate delivery of the pulses in vivo under a variety of conditions (transdermal, laparoscopic, catheter, etc.) currently exist (International patent applications WO 9922809A1, WO 9906101A1 [Gentronics Inc.]; WO 9901157A1, WO 9901157A1, and WO 9901158 [Rhone Poulenc Rorer S. A.].
More recently it has been found that exposure of human erythrocytes to short and intense electric pulses which facilitates transient permeabilisation also results in a dramatic sensitisation to low intensity ultrasound (WO/01/07011).